Hypoxia Improves Hair Inductivity of Dermal Papilla Cells via Nuclear NADPH Oxidase 4‐Mediated Reactive Oxygen Species Generation

Summary

Background

Dermal papilla cells (DPCs) play a key role in hair regeneration and morphogenesis. Therefore, tremendous efforts have been made to promote DPCsʼ hair inductivity

Objectives

The aim of this study was to investigate the mitogenic and hair inductive effects of hypoxia on DPCs and examine the underlying mechanism of hypoxia‐induced stimulation of DPCs.

Results

Hypoxia significantly increased the proliferation and delayed the senescence of DPCs via Akt phosphorylation and downstream pathways. Hypoxia upregulated the growth factor secretion of DPCs through mitogen‐activated protein kinase pathway. Hypoxia‐preconditioned DPCs induced the telogen‐to‐anagen transition in C₃H mice, and also enhanced hair neogenesis in a hair reconstitution assay. Injected GFP‐labeled DPCs migrated to outer‐root sheath of hair follicle, and hypoxia‐preconditioning increased the survival and migration of DPCs in vivo. Conditioned medium obtained from hypoxia increased the hair length of mouse vibrissa follicles via upregulation of alkaline phosphatase, vascular endothelial growth factor, and glial cell line‐derived neurotrophic factor. We examined the mechanism of this hypoxia‐induced stimulation, and found that reactive oxygen species (ROS) play a key role. For example, inhibiting of ROS generation by N‐acetyl‐L‐cysteine or diphenyleneiodonium treatment attenuated DPCsʼ hypoxia‐induced stimulation, but treatment with ROS donors induced mitogenic effects and anagen transition. NADPH oxidase 4 (NOX4) is highly expressed in DPCsʼ nuclear region, and NOX4 knockout by CRISPR‐Cas9 attenuated the hypoxia‐induced stimulation of DPCs.

Conclusions

Our results suggest that DPC culture under hypoxia has great advantages over normoxia, and is a novel solution for producing DPCs for cell therapy.

This article is protected by copyright. All rights reserved.

http://bit.ly/2MHiOSB